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Copper deficiency

Copper deficiency is a very rare hematological and neurological disorder.[1]
The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback".[2] Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.[3]

Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001.[9] They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patient`s paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar.
Sufferers typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction[7] or degeneration of the spinal cord (myelopathy).[2][10] Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing side way jerks and lunges.[11]

In brain MRI, there is often an increased T2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency.[2][7][12] T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both.[2][7] Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD).[10]Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12 deficiency is the cause of the spinal degeneration.[2] SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.[12]

Another common symptom of copper deficiency is peripheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso.[7][13] In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69-year-old patient had progressively worsened neurological symptoms.[14] These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception or sensation about the self’s orientation.[14] Many people suffering from the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient.[2][13] This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients dependent on wheel chairs or walking canes for mobility if there is lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.

Some patients suffering from copper deficiency have shown signs of vision and color loss.[13] The vision is usually lost in the peripheral views of the eye.[13] The bilateral vision loss is usually very gradual.[15][13] An optical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy or neurodegeneration.[13]

Bariatric surgery is a common cause of copper deficiency.[2][6] Bariatric surgery, such as gastric bypass surgery, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only as regards copper, but also for iron and vitamin B12 and many other nutrients.[2] The symptoms of copper deficiency myelopathy may take a long time to develop, sometimes decades before the myelopathy symptoms manifest.

Increased consumption of zinc is another cause of copper deficiency.[7]Zinc is often used for the prevention or treatment of common colds and sinusitis (inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment, and acne.[7] Zinc is found in many common vitamin supplements and is also found in denture creams.[7][15][16] Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc.[15][16]

Metallic zinc is the core of all United States currency coins, including copper coated pennies. People who ingest a large number of coins will have elevated zinc levels, leading to zinc-toxicity-induced copper deficiency and the associated neurological symptoms. This was the case for a 57-year-old woman diagnosed with schizophrenia. The woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.[17]

Menkes disease is a congenital disease that is a cause of copper deficiency.[4][7][18] Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body.[7] Menkes disease involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough.[4][18] Menkes disease is usually a fatal disease with most children dying within the first ten years of life.[4][18]

It is rarely suggested that excess iron supplementation causes copper deficiency myelopathy.[2]
Another rarer cause of copper deficiency is Coeliac disease, probably due to malabsorption in the intestines.[2]
Still, a large percentage, around 20%, of cases have unknown causes.[2]

There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.[2][10]

Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle.[10] The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase.[10] This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins.[10] The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy.[10]

The anemia caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitate its transfer across the basolateral membrane into circulation.[6] Another iron transporting enzyme is ceruloplasmin.[6] This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma.[6] Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding.[4] Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia.[6] Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize heme from ferric iron at the normal rate.[6] The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern.[6] This unusual pattern is also known as ringed sideroblastic anemia cells.

Zinc intoxication may cause anemia by blocking the absorption of copper from the stomach and duodenum.[2] Zinc also upregulates the expression of chelatormetallothionein in enterocytes, which are the majority of cells in the intestinal epithelium.[2] Since copper has a higher affinity for metallothionein than zinc, the copper will remain bound inside the enterocyte, which will be later eliminated through the lumen.[2] This mechanism is exploited therapeutically to achieve negative balance in Wilson’s disease, which involves an excess of copper.[2]

Copper deficiency is a very rare disease and is often misdiagnosed several times by physicians before concluding the deficiency of copper through differential diagnosis (copper serum test and bone marrow biopsy are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician.[2]
Copper deficiency can be treated with either oral copper supplementation or intravenous copper.[7] If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process.[7] People who suffer from zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal.[7] The progression of the neurological symptoms will be stopped by appropriate treatment, but often with residual neurological disability.